This invention relates to novel xanthone compounds, their preparation and use as a medicament. More particularly this invention is directed to the isolation of the novel xanthone natural product sootepenseone from Dasymaschalon sootepense Craib, Annonaceae, its identification and derivatization, and the use of sootepenseone and its derivatives as anticancer agents.
Cancer is perhaps one of the most active anti-human factor operating in the world today, and efforts are being made all over the scientific world to prevent and eradicate it.
New agents with chemotherapeutic value in the fight against cancer is obviously a medical problem of high importance. But the development of new drugs in the cancer field is a difficult task given that anticancer agents must be lethal to, or incapacitate tumor cells, but they should not cause excessive damage to normal cells. At present the state of knowledge in cancer biology and in medical chemistry does not warrant the designing of new classes of molecules which may be effective antitumor agents. Despite the great progress made in cancer biology, molecular pharmacology, pharmacokinetics, medical chemistry and allied fields, the knowledge sought after, is still elusive.
Since the concept of chemotherapeutic treatment of malignant diseases had come to the forefront during the last decades, plant principles and their derivatives have been intensively investigated by scientists all over the world as new antitumor inhibitors. Examples for important anticancer agents of plant origins are the alkaloids vincaleukoblastine (vinblastine) and leurocristine (vincristine), both isolated from Catharanthus roseus. A comprehensive review on natural products as anticancer agents is given by Shradha Sinha and Audha Jain, in: Progess in Drug Research, Vol. 42, pages 53-132 (1994) Basel (Switzerland).
In accordance with the present invention there are provided novel cytotoxic xanthone compounds of the general formula (I) 
wherein
R1 is a hydrogen atom; a methyl group (xe2x80x94CH3), a C2-C6 alkyl residue, a formyl group (xe2x80x94CHO); an acetyl residue (xe2x80x94COCH3), xe2x80x94COxe2x80x94C2-6-alkyl, COxe2x80x94C3-8-cycloalkyl, xe2x80x94COxe2x80x94C6-18-aryl or xe2x80x94COxe2x80x94C7-24-aralkyl residue each having optionally one or more substituents selected from the group consisting of xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6-alkyl, xe2x80x94N(C1-6-alkyl)2, xe2x80x94NHC6-14-aryl, xe2x80x94N(C6-14-aryl)2, xe2x80x94N(C1-6-alkyl)(C6-14-aryl), xe2x80x94NHCOR2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R3 , xe2x80x94(CS)R4, xe2x80x94F, xe2x80x94CI, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94Oxe2x80x94(CO)R5, xe2x80x94Sxe2x80x94C1-6-alkyl, xe2x80x94Sxe2x80x94C6-14-aryl, xe2x80x94SOR6, and xe2x80x94SO2R7, wherein R2 to R7 stands independently of each other for a hydrogen atom, xe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94NH2, xe2x80x94NHC1-6-alkyl, xe2x80x94N(C1-6-alkyl)2, xe2x80x94NHC6-14-aryl, xe2x80x94N(C6-14-aryl)2, xe2x80x94N(C1-6-alkyl)(C6-14-aryl), xe2x80x94Sxe2x80x94C1-6-alkyl, xe2x80x94Sxe2x80x94C6-14-aryl residue;
a xe2x80x94COOxe2x80x94C1-6-alkyl residue having optionally one or more substituents selected from the group consisting of xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6-alkyl, xe2x80x94N(C1-6-alkyl)2, xe2x80x94NHC6-14-aryl, xe2x80x94N(C6-14-aryl)2, xe2x80x94N(C1-6-alkyl)(C6-14-aryl), xe2x80x94NHCOR8, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R9, xe2x80x94(CS)R10, xe2x80x94F, xe2x80x94CI, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94Oxe2x80x94(CO)R11, xe2x80x94Sxe2x80x94C1-6-alkyl, xe2x80x94Sxe2x80x94C6-14-aryl, xe2x80x94SOR12, and xe2x80x94SO2R13, wherein R8 to R13 stands independently of each other for a hydrogen atom, xe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94NH2, xe2x80x94NHC1-6-alkyl, xe2x80x94N(C1-6-alkyl)2, xe2x80x94NHC6-14-aryl, xe2x80x94N(C6-14-aryl)2, xe2x80x94N(C1-6-alkyl)(C6-14-aryl) xe2x80x94Sxe2x80x94C1-6-alkyl, xe2x80x94Sxe2x80x94C6-14-aryl residue;
a xe2x80x94CONR14R15 residue wherein R14 and R15 stand independently of each other for a hydrogen atom, xe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94NH2, xe2x80x94NHC1-6-alkyl, N(C1-6-alkyl)2, xe2x80x94NHC6-14-aryl, xe2x80x94N(C6-14-aryl)2, xe2x80x94N(C1-6-alkyl)(C6-14-aryl), xe2x80x94Sxe2x80x94C6-14-aryl residue;
or a counter cation selected from the group consisting of an alkali or earth alkali metal such as Li, Na, K, Ca, Mg, NR16R17R18R19(+) wherein R16 to R19 stands independently of each other for a hydrogen atom or a C1-C6-alkyl residue;
R2 and R3 either form part of the C17xe2x95x90C18 -double bond or are each hydrogen, or a tautomer, an enantiomer, an stereoisomer or a physiologically acceptable salt or a solvate thereof or mixtures thereof.
In the case of a compound according to formula 1 above in the form of a phenolate with a di- or multivalent counter cation, the remaining positive charge can be compensated by association with a physiologically acceptable anion such as CI- or OH-.
The novel compound according to formula I, wherein R1 is a hydrogen atom and R2 and R3 form part of the C17-C18 -double bound, has been given the name sootepenseone (1).
According to another aspect of the invention there is provided a process for manufacturing a compound according to formula I by isolation of sootepenseone (1) from the leaves of Dasymaschalon sootepenseone Craib, Annonaceae and its subsequent derivatization.
The present invention further provides the use of the compounds according to formula (I) as medicament, in particular for the treatment of cancer diseases.
The present invention further provides pharmaceutical formulations, comprising an effective amount of a compound according to formula (I) for treating a patient in need thereof. As used herein, an effective amount of a compound according to formula (I) is defined as the amount of the compound which, upon administration to a patient, inhibits growth of tumor cells, kills malignant cells, reduces the volume or size of the tumors or eliminates the tumor entirely in the treated patient.
Thus, the substantially pure compounds in accordance with the invention can be formulated into dosage forms using pharmaceutically acceptable carriers for oral, topical or parenteral administration to patients in need of oncolytic therapy.
In a preferred embodiment, the patient is a mammal, in particular a human.
The effective amount to be administered to a patient is typically based on body surface area, patient weight, and patient condition. The interrelationship of dosages for animals or humans (based on milligrams per meter squared of body surface) is described by Freireich, E. J. et al., Cancer Chemother. Rep., 50 (4) 219 (1966). Body surface area may be approximately determined from patient height and weight (see e.g. Scientific Tables, Geigy Pharmaceuticals, Ardly, N.Y., pages 537-538 (1970)). Preferred dose levels will also depend on the attending physicians assessment of both the nature of the patient""s particular cancerous condition and the overall physical condition of the patient. Effective antitumor doses of the present xanthone compounds range from 1 microgram per kilogram to about 5000 micrograms per kilogram of patient body weightmilligram, more preferably between 2 micrograms to about 1000 micrograms per kilogram of patient body weight.
Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage and the posibility of co-usage with other therapeutic treatments including other anti-tumor agents, and radiation therapy.
The present pharmaceutical formulation may be administered intravenous, intramuscular, intradermal, subcutaneous, intraperitoneally, topical, or intravenous in the form of a liposome.
Examples of dosage forms include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier. Additional solubilizing agents well-known to those familiar with the art can be utilized as pharmaceutical excipients for delivery of the active agent. Alternatively, the present compounds can be chemically modified to enhance water solubility, for example, by formation of pharmaceutically acceptable phenolate salts.
The present compounds can also be formulated into dosage forms for other routes of administration utilizing well-known methods. The pharmaceutical compositions can be formulated, for example, in dosage forms for oral administration in a capsule, a gel seal or a tablet. Capsules may comprise any well-known pharmaceutically acceptable material such as gelatin or cellulose derivatives. Tablets may be formulated in accordance with conventional procedure by compressing mixtures of the active agent and solid carriers, and lubricants well-known to those familiar with the art. Examples of solid carriers include starch, sugar, bentonite. The compounds of the present invention can also be administered in a form of a hard shell tablet or capsule containing for example, lactose or mannitol as a binder and a conventional fillers and tableting agents.
The terms xe2x80x9ceffective amountxe2x80x9d and xe2x80x9ceffective dosexe2x80x9d as referring to the treatment of animals is defined herein to mean those quantities of alkaloid which will cause remession or inhibition of growth of the cancer disease in the animal to which it is administered, without imparting an untolerable toxic response. The effective amount may vary with the way of administration, the administration schedule, the kind of tumor, and other related factors, all of which may be varied without departing from the scope or operativeness of the invention. Generally an effective dose would be one within the range of about 0.001-100.0 mg/kg of body weight/day.
The terms xe2x80x9ccancerxe2x80x9d or xe2x80x9ctumorxe2x80x9d as used herein include, but are in no way limited to, adrenocarcinomas, glioblastomas (and other brain tumors), breast, cervical, colorectal, endometrial, gastric, liver, lung (small cell and non-small cell), lymphomas (including non-hodgkin""s, Burkitt""s, diffuse large cell, follicular and diffuse Hodgkin""s), melanoma (metastatic), neuroblastoma, osteogenic sarcoma, ovarian, retinoblastoma, soft tissue sarcomas, testicular and other tumors which respond to chemotherapy.
Other objects and advantages of the invention will become readily apparent from the ensuing description.
The inventive compounds according to formula (I) have a pentacyclic xanthone ring system (see for a review: Sultanbawa, M.U.S., Xanthonoids of tropical plants, Tetrahedron 36 (1980) 1465-1506). The following natural compounds are reported as having a similar ring system:
Gambogic acid (2), isolated from Garcinia hanburyi (see Amorosa, M. et al., Ann. Chim. (Rome), 1966, 56, 232; Ahmad, A. S. et al., J. Chem. Soc. (C), 1966, 772 (structure); Arnone, A. et al., Tetr. Lett., 1967, 4201 (pmr data, structure), morellin (3) isolated from Garcinia morella (see: Rao, B. S., J. Chem. Soc, 1937, 853 (isolation); Kartha, G. et al., Tetr. Lett., 1963, 459 (cryst. structure)); Nair, P. M. et al., Indian J. Chem., 1964, 2, 402 (structure)), hanburin (4) isolated from Garcinia hanburyi (see: Asano, J. et al., Phytochemistry, 1996, 41, 815 (isolation, uv, ir, pmr, cmr data) and forbesione (5) isolated from Garcinia forbesii (see: Yuan-Wah eong, Leslie J. Harrison, Graham J. Bennett and Hugh T.-W. Tan, J. Chem. Research (S) 1996, 392-393).
These compounds have at C-5 an isoprenyl side chain in common with a hydrogen bonded phenolic hydroxy group. Morellin (3) and gambogic acid (2) have a chromene ring system in common. All compounds (2) to (5) have in common a bicyclo[2.2.2]octene carbon skeleton fused to a 2,2-dimethyl-tetrahydrofuran ring system (see FIG. 1).
However, these compounds show significant structural differences as compared to the compounds according to formula I of the present invention:
1.) the C-5 isoprenyl side chain is oxidized to an aldehyde as in (3) or to a carboxyclic acid as in (2);
2.) the condensed dihydrofuran ring in 3,4-position is missing as in (4) or instead a pyranone ring is present in the 2,3-position as in (3)
3.) the ring system is substituted with an additional isoprenyl side chain at C-5 as in (3) and (5)
By contrast, the compounds of the present invention contain fully substituted dihydrofuran rings except at carbon 2xe2x80x2, fused to the modified xanthone ring system.
For the taxonomy of Dasymaschalon sootepense Craib see V. H. Heywood, xe2x80x9cFlowering Plants of the Worldxe2x80x9d, University Press, Oxford, 1978.
Surprisingly, the compounds of the present invention show remarkable antitumor activity. Moreover, the present compounds have a low toxicity.
Thus the xanthone compounds according to the present invention are new and involve an inventive step.
The structures of (2) to (5) are summarized below: 